Activation of Indian hedgehog promotes chondrocyte hypertrophy and upregulation of MMP-13 in human osteoarthritic cartilage

Wei, Fulan; Zhou, Jingming; Wei, Xiaochun; Zhang, Juntao; Fleming, Braden C.; Terek, Richard M.; Pei, Ming; Chen, Qian; Liu, Tao; Wei, Lei

doi:10.1016/j.joca.2012.03.010

Cited by 126 publications

(168 citation statements)

References 32 publications

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“…A recent study reported that Ihh is upregulated in human OA cartilage and synovial fluid, and that the elevated level correlates with OA progression (40). The abnormality observed in Ihh-/-mice is an increase in the fraction of chondrocytes which are post-mitotic, hypertrophic chondrocytes.…”

Section: Effect Of Indian Hedgehog On Articular Chondrocyte Degeneratmentioning

confidence: 99%

Recent advances in the understanding of molecular mechanisms of cartilage degeneration, synovitis and subchondral bone changes in osteoarthritis

Wei

Bai

2016

Connective Tissue Research

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Osteoarthritis (OA), the most common form of degenerative joint disease, is linked to high morbidity. It is predicted to be the single greatest cause of disability in the general population by 2030. The development of disease-modifying therapy for OA currently face great obstacle mainly because the onset and development of the disease involve complex molecular mechanisms. In this review, we will comprehensively summarize biological and pathological mechanisms of three key aspects: degeneration of articular cartilage, synovial immunopathogenesis, and changes in subchondral bone. For each tissue, we will focus on the molecular receptors, cytokines, peptidases, related cell, and signal pathways. Agents that specifically block mechanisms involved in synovial inflammation, degeneration of articular cartilage, and subchondral bone remodeling can potentially be exploited to produce targeted therapy for OA. Such new comprehensive agents will benefit affected patients and bring exciting new hope for the treatment of OA.

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Section: Effect Of Indian Hedgehog On Articular Chondrocyte Degeneratmentioning

confidence: 99%

Recent advances in the understanding of molecular mechanisms of cartilage degeneration, synovitis and subchondral bone changes in osteoarthritis

Wei

Bai

2016

Connective Tissue Research

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“…In particular, the production of collagenases such as MMP13 and aggrecanase-2 (ADAMTS5) by potent pro-inflammatory cytokines such as interleukin (IL)-1β is a major mediator of cartilage destruction [5][6][7]. OA is usually accompanied by increased expression of collagen type X, Runx2, vascular endothelial growth factor (VEGF) and increased activity of alkaline phosphatase, with decreased expression of collagen type II and aggrecan, and other early chondrocyte marker genes such as Sox9 [8][9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Osthole Inhibits Proliferation and Induces Catabolism in Rat Chondrocytes and Cartilage Tissue

Song

Wei

et al. 2015

Cell Physiol Biochem

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Background/Aims: Cartilage destruction is thought to be the major mediator of osteoarthritis. Recent studies suggest that inhibition of subchrondral bone loss by anti-osteoporosis (OP) drug can protect cartilige erosion. Osthole, as a promising agent for treating osteoporosis, may show potential in treating osteoarthritis. The purpose of this study was to investigate whether Osthole affects the proliferation and catabolism of rat chondrocytes, and the degeneration of cartilage explants. Methods: Rat chondrocytes were treated with Osthole (0 μM, 6.25 μM, 12.5 μM, and 25 μM) with or without IL1-β (10ng/ml) for 24 hours. The expression levels of type II collagen and MMP13 were detected by western Blot. Marker genes for chondrocytes (A-can and Sox9), matrix metalloproteinases (MMPs), aggrecanases (ADAMTS5) and genes implicated in extracellular matrix catabolism were evaluated by qPCR. Cell proliferation was assessed by measuring proliferating cell nuclear antigen (PCNA) expression and fluorescence activated cell sorter. Wnt7b/β-catenin signaling was also investigated. Cartilage explants from two-week old SD rats were cultured with IL-1β, Osthole and Osthole plus IL-1β for four days and glycosaminoglycan (GAG) synthesis was assessed with toluidine blue staining and Safranine O/Fast Green FCF staining, collagen type II expression was detected by immunofuorescence. Results: Osthole reduced expression of chondrocyte markers and increased expression of MMP13, ADAMTS5 and MMP9 in a dose-dependent manner. Catabolic gene expression levels were further improved by Osthole plus IL-1β. Osthole inhibited chondrocyte proliferation. GAG synthesis and type II collagen were decreased in both the IL-1β groups and the Osthole groups, and significantly reduced by Osthole plus IL-1β. Conclusions: Our data suggested that Osthole increases the catabolism of rat chondrocytes and cartilage explants, this effect might be mediated through inhibiting Wnt7b/β-catenin pathway.

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“…Hedgehog signalling is activated in OA chondrocytes and its overexpression promotes chondrocyte hypertrophy and cartilage damage in mice resembling human OA 14 21. In contrast, pharmacological or genetic inactivation of hedgehog signalling reduces the severity of OA and thus might represent a future treatment option 22 23…”

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confidence: 99%

Inhibition of Notch1 promotes hedgehog signalling in a HES1-dependent manner in chondrocytes and exacerbates experimental osteoarthritis

et al. 2016

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ObjectivesNotch ligands and receptors have recently been shown to be differentially expressed in osteoarthritis (OA). We aim to further elucidate the functional role of Notch signalling in OA using Notch1 antisense transgenic (Notch1 AS) mice.MethodsNotch and hedgehog signalling were analysed by real-time PCR and immunohistochemistry. Notch-1 AS mice were employed as a model of impaired Notch signalling in vivo. Experimental OA was induced by destabilisation of the medial meniscus (DMM). The extent of cartilage destruction and osteophyte formation was analysed by safranin-O staining with subsequent assessment of the Osteoarthritis Research Society International (OARSI) and Mankin scores and µCT scanning. Collagen X staining was used as a marker of chondrocyte hypertrophy. The role of hairy/enhancer of split 1 (Hes-1) was investigated with knockdown and overexpression experiments.ResultsNotch signalling was activated in human and murine OA with increased expression of Jagged1, Notch-1, accumulation of the Notch intracellular domain 1 and increased transcription of Hes-1. Notch1 AS mice showed exacerbated OA with increases in OARSI scores, osteophyte formation, increased subchondral bone plate density, collagen X and osteocalcin expression and elevated levels of Epas1 and ADAM-TS5 mRNA. Inhibition of the Notch pathway induced activation of hedgehog signalling with induction of Gli-1 and Gli-2 and increased transcription of hedgehog target genes. The regulatory effects of Notch signalling on Gli-expression were mimicked by Hes-1.ConclusionsInhibition of Notch signalling activates hedgehog signalling, enhances chondrocyte hypertrophy and exacerbates experimental OA including osteophyte formation. These data suggest that the activation of the Notch pathway may limit aberrant hedgehog signalling in OA.

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Activation of Indian hedgehog promotes chondrocyte hypertrophy and upregulation of MMP-13 in human osteoarthritic cartilage

Cited by 126 publications

References 32 publications

Recent advances in the understanding of molecular mechanisms of cartilage degeneration, synovitis and subchondral bone changes in osteoarthritis

Recent advances in the understanding of molecular mechanisms of cartilage degeneration, synovitis and subchondral bone changes in osteoarthritis

Osthole Inhibits Proliferation and Induces Catabolism in Rat Chondrocytes and Cartilage Tissue

Inhibition of Notch1 promotes hedgehog signalling in a HES1-dependent manner in chondrocytes and exacerbates experimental osteoarthritis

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